Nuclear Factor-kB Activation in Airway Epithelium Induces Inflammation and Hyperresponsiveness

Rationale: Nuclear factor (NF)-kB is a prominent proinflammatory transcription factor that plays a critical role in allergic airway disease. Previous studies demonstrated that inhibition of NF-kB in airway epithelium causes attenuation of allergic inflammation. Objectives: We sought to determine if selective activation of NF-kB within the airway epithelium in the absence of other agonists is sufficient to cause allergic airway disease. Methods: A transgenic mouse expressing a doxycycline (Dox)inducible, constitutively active (CA) version of inhibitor of kB (IkB) kinase-b (IKKb) under transcriptional control of the rat CC10 promoter, was generated. Measurements and Main Results: After administration of Dox, expression of the CA-IKKb transgene induced the nuclear translocation of RelA in airway epithelium. IKKb-triggered activation of NF-kB led to an increased content of neutrophils and lymphocytes, and concomitantproduction ofproinflammatorymediators, responses thatwere not observed in transgenic mice not receiving Dox, or in transgenenegative littermate control animals fed Dox. Unexpectedly, expression of the IKKb transgene in airway epithelium was sufficient to cause airway hyperresponsiveness and smooth muscle thickening in absence of an antigen sensitization and challenge regimen, the presence of eosinophils, or the induction of mucus metaplasia. Conclusions: Thesefindingsdemonstrate that selective activation NFkB in airway epithelium is sufficient to induce airway hyperresponsiveness and smooth muscle thickening, which are both critical features of allergic airway disease.